Heterocycles [3+2]-Cycloadditions of N -Cyano Sulfoximines with 1,3-Dipoles

: Involving the cyano group of N -cyano sulfoximines in [3+2]-cycloaddition reactions with 1,3-dipoles provides practical routes for the construction of 5-membered heterocycles bearing sulfoximinoyl moieties. An ytterbium-catalyzed cycloaddition utilizing hydrazonoyl chlorides was developed, as well for 24 h. Then, the solvent was removed under reduced pressure, and the reaction mixture subjected to flash column chromatography on silica gel using the specified gradient. We are grateful to the Alexander von Humboldt Foundation for support of K. R. (AvH research award) and thank S. Huda, A. Krohmer, and F. Brosge (all RWTH Aachen University) for their practical work and assistance in preparing starting materials.


Introduction
Being structurally related to the ubiquitous sulfamoyl group, the sulfoximinoyl moiety has in turn found significant interest in pharmaceutical and agrochemical industry. [1,2] Possessing a potential stereogenic sulfur and an additional site for further functionalization at the nitrogen atom, sulfoximines can be used to increase structural diversity, enable additional bonding interactions or generally improve pharmacokinetic properties. [1a] BSO, [3] Roniciclib, [1a] and Gö 4962 [4] are examples for medicinal compounds, while Sulfoxaflor [5] is employed as pesticide (Figure 1). as a reaction involving imidoyl chlorides proceeding without the aid of a catalyst. Following these protocols, a range of sulfoximines with N-1,2, 4-triazolyl and N-1,2,4-oxadiazolyl substituents was prepared.

Results and Discussion
Hydrazonoyl chlorides are known to undergo dehydrohalogenation reactions providing highly reactive nitrilimines. [27] If those react with nitriles by 1,3-dipolar cycloaddition, 1,2,4-triazoles result. For the study reported here, we chose sulfoximine 5a and hydrazonoyl chloride 6a as representative starting materials. As numerous methods for the dehydrohalogenation of the betaine precursors exist, the rate of release of the active 1,3dipole can be tailored to the reactivity of the dipolarophile. Our initial attempt revealed that refluxing the reactants in toluene was insufficient, with 6a being almost fully recovered (Table 1, entry 1). Subsequently, various bases were added (Table 1, entries 2-4), and NaHCO 3 was identified as most effective, yielding N-triazolyl sulfoximine 7a in 59 %. Being inspired by a report of Su and co-workers, [28] Yb(OTf ) 3 was tested as catalyst. Even without base, the presence of 10 mol-% of Yb(OTf ) 3 led to 7a in 44 % yield (Table 1, entry 5). Most likely, the Lewis acid supported the cycloaddition reaction by activation of 5a through coordination to the N-cyano group. Alternatively, Yb(OTf ) 3 facili-  Figure 2. First, the sulfoximine structure was varied, and hydrazonoyl chloride 6a was used as coupling partner. In the series of methyl sulfoximines (leading to products 7a-h) neither electron-donating nor -withdrawing groups on the arene showed a significant effect on the efficiency of the heterocyclization. In most cases, the yields were high (with up to 99 %). The only exceptions were 4-acetyl and 4-nitro-substituted substrates 5d and 5h. Whereas the former afforded product 7d in 84 % yield, the reaction with the latter provided only unidentified degradation products. The failure of converting 4-nitrophenyl-substituted Ncyano sulfoximine 5h is in line with observations described later related to the attempted synthesis of 9e (see Figure 4) indicating an intrinsic instability of compounds with such substitution pattern. S-Phenyl sulfoximines with S-ethyl, S-isopropyl, and Scyclopropyl groups reacted as well leading to the corresponding product 7i-k in yields of 98 %, 89 %, and 85 %, respectively.  Table 1, entry 10).
Applying sulfoximine 5a in reactions with other hydrazonoyl chlorides 6 revealed the flexibility of the approach (Figure 2). In general, the yields of the corresponding products (7l-7q) were high (> 86 %) again, with the only exception of nitrocontaining targeted product 7o where decomposition was observed.
With the intention to expand the reaction portfolio of Ncyano sulfoximines with in-situ formed propargyl-type 1,3-di-poles obtained by dehydrohalogenations of respective betaine precursors we turned our attention to a potential use of imidoyl chlorides. In relation to the studies by Saravanan and co-workers, [19,20] this approach presented a synthetic alternative towards N-1,2,4-oxadiazolyl-sulfoximines.
Imidoyl chlorides are readily available by chlorination of aldoximes, and their subsequent dehydrohalogenations leads to nitrile oxides, which undergo a wide range of 1,3-dipolar cycloaddition reactions. [29] Usually, nitrile oxides are generated at room temperature and an equimolar amount of the dipolarophile is sufficient to provide the products in high yield and selectivity. The attempt to follow this protocol here with N-cyano sulfoximine 5a and imidoyl chloride 8a as starting materials remained unsuccessful. In all cases, the yield of N-1,2,4-oxadiazolyl-sulfoximine 9a remained unsatisfying, independent of the type of base or the solvent ( Table 2, entries 1-8). At best, 9a was obtained in 44 % yield, when the transformation was carried out in DCM in the presence of sodium bicarbonate (Table 2, entry 4). Attempts to mediate or catalyze the reaction with metal salts (such as CuCl in the absence or presence of amine ligands) were also unsuccessful (details not shown). However, increasing the temperature proved beneficial, being in line with a thermal activation of the intended 1,3-dipolar cycloaddition. Finally, product 9a could be isolated in 94 % yield after carrying out the reaction in toluene at 120°C for 24 h (Table 2, entry 9). The addition of a base proved unnecessary. The molecular structure of 9a (Figure 3) was unequivocally proven by X-ray crystal structure analysis. [30] Next, the optimized conditions (Table 2, entry 9) were applied on other substrate combinations. The results are summarized in Figure 4. Again, the sulfoximine structure was varied first. In the series of S-aryl-S-methyl sulfoximines, the yields of the corresponding N-oxadiazolyl-sulfoximines 9a-i showed a wider distribution than those for the previously described Ntriazolyl sulfoximines 7 (Figure 2). Generally, sulfoximines with electron-donating substituents on the arene performed better than those with electron-withdrawing substituents. For exam- Figure 3. X-ray crystal structure of product 9a. [30] ple, product 9f having a methoxy group in the 4 position of the S-aryl was obtained in 97 % yield. In contrast, 9h bearing a 4-acetyl substituent was only formed in 48 %. Similar trends were observed with the halogenated derivatives 9b-d. Also in this series, the nitro-containing product (9e) could not be isolated due to decomposition of sulfoximine 5e under these otherwise optimal conditions. Presumably due to a steric effect the yields of 9f and 9g differ significantly (97 % vs. 67 %). Both products have methoxy-groups on the arene, but while the former bears the substituent on the 4 position, the latter has it in 2 position leading to a more pronounced steric impact. [31] An analogous behavior was seen when the S-methyl group on the sulfoximine is substituted by S-ethyl and S-cyclopropyl. While 9a (with S-methyl) and 9j (with S-ethyl) are formed in almost identical yields of 95 % and 97 %, respectively, 9k bearing a sterically more demanding α-branched cyclopropyl substituent is only isolated in 70 % yield. Also halo-containing aryl imidoyl chlorides reacted with sulfoximine 5a albeit the yields of the resulting products 9l-n remained only moderate (39-49 %). Presumably, the dimerization rate of the intermediately formed nitrile oxide was too high to compete with the desired cycloaddition at the N-cyano group of sulfoximine 5a. Substrate decomposition was observed in the attempt to react aliphatic acetimidoyl chloride (9o) with N-cyano sulfoximine 5a under the standard conditions. As a result, parts of 5a could be recovered, and 9o remained inaccessible.  Table 2, entry 9).

Conclusions
In summary, sulfoximines with N-bound five-membered heterocycles have been prepared by [3+2] cycloaddition reactions of N-cyano sulfoximines and nitrilium betaines derived from hydrazonoyl and imidoyl chlorides. While the former type of transformations benefits from the presence of catalytic amounts of Yb(OTf ) 3 , the latter proceed metal-free. Future investigations will focus on applying other 1,3-dipoles on Ncyano sulfoximines with the goal of expanding the chemical space around this interesting class of compounds.

Experimental Section
Typical Procedure for the Synthesis of N-1,2,4-Triazolyl Sulfoximines 7: To an oven-dried 10 mL tube equipped with a stirring bar was added N-cyano sulfoximine 5 (0.2 mmol), hydrazonoyl chloride 6 (0.3 mmol, 1.5 equiv.), NaHCO 3 (25.2 mg, 0.3 mmol, 1.5 equiv.), ytterbiumtriflate (12.4 mg, 0.02 mmol, 0.1 equiv.) and benzene (0.5 mL). After sealing, the tube was placed in a preheated aluminum heating block, and the reaction mixture was stirred at 120°C for 24 h. Then, the solvent was removed under reduced pressure, and the reaction mixture subjected to flash column chromatography on silica gel using the specified gradient. N-1,2,4-Oxadiazolyl Sulfoximines 9: To an oven-dried 10 mL tube equipped with a stirring bar was added N-cyano sulfoximine 5 (0.2 mmol), imidoyl chloride 8 (0.4 mmol, 2.0 equiv.) and toluene (0.5 mL). The tube was sealed, placed in a preheated aluminum heating block, and the reaction was stirred at 120°C for 24 h. Then, the solvent was removed under reduced pressure, and the reaction mixture subjected to flash column chromatography on silica gel using the specified gradient.